Ilka Pinz, PhD
Faculty Scientist II
Center for Molecular Medicine
Pinz Lab
Investigating mechanisms leading to lipotoxic cardiomyopathy.
The research focus of my laboratory is on mechanisms leading to lipotoxic cardiomyopathy. With the growing incidence of obesity, and the burden this puts on the health care system, it is important to understand the mechanisms by which certain fatty acids and their metabolites change signaling pathways in cardiomyocytes that cause a decline in contractile performance. In particular, we focus on highly organized membrane micro-domains called caveolae. Caveolae are small flask-like membrane invaginations that on the intracellular membrane leaflet are lined by caveolin proteins. In the heart caveolin-1 and -3 are expressed and are responsible for maintaining caveolae structure. Using different high fat diets we investigate how a change in the membrane lipid composition affects caveolin proteins and what consequences this has for cardiac contractile performance. We utilize in vivo imaging techniques such as echocardiography and magnetic resonance imaging to measure cardiac contractile performance in the live mouse. To determine ex vivo contractile performance we use the Langendorff mode. We have determined that the loss of cardiac caveolin-3 by high fat feeding is part of the mechanism for lipid-induced cardiac contractile dysfunction. The figure below shows the intracellular localization of the caveolin proteins in isolated adult mouse cardiomyocytes from mice fed different high fat diets; MCT control diet, which is a high fat control diet containing only triglycerides, and palmitate diet containing about 11% of palmitate.
Signaling and Caveolin
A separate part of our work focuses on signaling proteins and receptors that bind to the caveolin scaffolding domain (CSD domain) in caveolin-3. This includes the insulin receptor and endothelial nitric oxides synthase (eNOS). For both proteins we can demonstrate that the activity and localization depends on the presence of caveolin-3 at the plasma membrane. This work has implications for vascular disease and for diabetes, two of the most common co-morbidities of obesity.
In our future work, we want to investigate how the lipid-induced loss of caveolin proteins can be prevented and what a potential pharmacological treatment to replace caveolin-3 in the heart may entail.